PROJECT SUMMARY ABSTRACT Approximately 1.7 million individuals sustain a traumatic brain injury (TBI) requiring medical attention every year in the United States. The majority of TBI injuries are mild in severity, yet nearly half of these individuals report residual disability from post-concussive symptoms that can persist for years after a traumatic injury. Post-traumatic headache (PTH) is the most common of these symptoms and is the most frequent type of post-traumatic pain in veteran and civilian populations with mild TBI (mTBI), where prevalence rates average 58%. Nearly half of those with mTBI and PTH also suffer from comorbid neck pain, yet the pathophysiologic processes leading to the development of chronic head and neck pain following a traumatic injury remain unclear. We postulate that nociceptive input from chronically deconditioned and painful cervical muscles can exacerbate PTH when coupled with impaired central pain processing networks in patients with comorbid head and neck pain resulting from mTBI. This project will be the first to concurrently examine structural and functional impairments in the central nervous system (brain) and periphery (cervical muscles) for clinically distinct subgroups of individuals with and without PTH and comorbid neck pain. Advanced magnetic resonance imaging (MRI) techniques will be used to compare (1) brain structure and functional connectivity between regions involved in descending pain modulation and the default mode network, and (2) markers of muscle quality and deconditioning in the cervical spine. We will also examine differences in the efficiency of conditioned pain modulation, and quantify the strength of association between MRI markers of brain and muscle impairments and the clinical severity of PTH. Findings from this developmental investigation will provide the foundation for a new line of research to assess whether subgroups of patients with PTH can benefit from multi-modal therapeutic approaches to address underlying impairments in distinct, yet related physiologic systems.